社会竞争失败病因学的抑郁症树鼩模型

抑郁症是一种常见精神疾病,主要表现为持续两周以上的情绪低落。世界卫生组织预测在2030年抑郁症的疾病负担将高居所有疾病、伤残总负担的榜首。抑郁症面临三大难题:1)发病机理不完全清楚,因而缺乏有效的预测预防途径和生物学诊断;2)现有单胺类抗抑郁症药物起效慢,也可能导致患者自杀风险增加;3)缺乏副作用小的非单胺类快速起效抗抑郁症药物。针对这三大难题,长期以来,应用抑郁症啮齿类模型的众多研究并未取得实质性进展,至少部分因素归咎于啮齿类与人类大脑功能的极大种属差异。树鼩是灵长类近亲,具有更接近于人类的大脑功能。本文针对抑郁症发病机理假说、临床表象和抗抑郁症药物疗效等内容,综述了社会竞争失败病因学的抑郁症树鼩模型可能会具有更好的疾病同源性、表象一致性和药物预见性。这一被长期忽视的抑郁症树鼩模型尽管还需要进一步完善,但对其进一步深入研究可能为解决抑郁症的三大难题提供了一条新途径。     

Synthesis,evaluation and CoMFA/CoMSIA study of nitrofuranyl methyl N-heterocycles as novel antitubercular agents

A series of novel nitrofuranyl methyl N-heterocycles based on the structure of IIIM-MCD-211 were designed and synthesized. Compounds 6d, 8b and 12a show excellent activity against MTB H37Rv strain (MIC: 0.031–0.062?μg/mL) roughly comparable to INH and IIIM-MCD-211. In addition, a three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on the above mentioned chemical series employing comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques. The developed CoMFA and CoMSIA models display high external predictability (r²_pred of 0.954 and 0.935, respectively) and good statistical robustness. More importantly, the newly designed compounds 16a and 16b (MIC: <0.016?μg/mL) based on the two models, as expected, were found to be more active than 12a and IIIM-MCD-21. Design and synthesis of more potent nitrofuranyl methyl N-heterocycles as anti-TB agents are currently in progress.     

Predictive value of circulating miR-328 and miR-134 for acute myocardial infarction

MicroRNA (miRNAs) is demonstrated to be present in the blood of humans and has been increasingly suggested as a novel biomarker for various pathological processes in the heart, including myocardial infarction, myocardial remodeling and progression to heart failure. In this study, we aim to evaluate the diagnostic and prognostic value of circulating miR-328 and miR-134 in patients with acute myocardial infarction (AMI). Circulating levels of miR-328 and miR-134 were detected by quantitative real-time PCR in plasma samples from 359 AMI patients and 30 healthy volunteers. Concentrations of high-sensitivity cardiac troponin T (hs-cTnT) were measured using electrochemiluminescence-based methods. MiRNAs were assessed for discrimination of a clinical diagnosis of AMI and for association with primary clinical endpoint defined as a composite of cardiogenic death and development of heart failure within 6 months after infarction. Results showed that levels of plasma miR-328 and miR-134 were significantly higher in AMI patients than in healthy controls. Receiver operating characteristic curve analyses showed significant diagnostic value of miR-328 and miR-134 for AMI. However, neither of them was superior to hs-cTnT for the diagnosis. Additionally, increased miRNA levels were strongly associated with increased risk of mortality or heart failure within 6 months for miR-328 (OR 7.35, 95 % confidence interval 1.07–17.83, P < 0.001) and miR-134 (OR 2.28, 95 % confidence interval 1.03–11.32 P < 0.001). In conclusion, circulating miR-328 and miR-134 could be potential indicators for AMI, and the miRNA levels are associated with increased risk of mortality or development of heart failure.     

Allele-specific targeting of hsa-miR-657 to human IGF2R creates a potential mechanism underlying the association of ACAA-insertion/deletion polymorphism with type 2 diabetes

The biological mechanism of a recent discovered association of type 2 diabetes with the ACAA-insertion/deletion polymorphism at the 3′UTR of the IGF2R gene has remained unclear. A very recently emerging novel polymorphic control layer by microRNAs (miRNAs) makes it possible to elucidate this issue. In this study, a prediction by web tools MicroInspector and miRanda demonstrated that DNA sequence polymorphism (DSPs) ACAA-insertion/deletion in IGF2R 3′UTR is located within the hsa-miR-657 and hsa-miR-453 binding sites. And luciferase reporter assay revealed that hsa-miR-657 acts directly at the 3′UTR of the IGF2R. Furthermore, ACAA-deletion exerted a further repression compared with ACAA-insertion, indicating that hsa-miR-657 regulates IGF2R gene expression in a polymorphic control manner. Importantly, we also demonstrated that hsa-miR-657 can translationally regulate the IGF2R expression levels in Hep G2 cells. Thus, our findings testify the possibility that the ACAA-insertion/deletion polymorphism may result in the change of IGF2R expression levels at least in part by hsa-miR-657-mediated regulation, contributing to the elucidation for the pathogenesis of type 2 diabetes and raise the possibility that miRNAs or in combination with functional DNA sequence polymorphism may be valuable in the treatment of human type 2 diabetes.     

Overexpression of miR‐483‐5p/3p cooperate to inhibit mouse liver fibrosis by suppressing the TGF‐β stimulated HSCs in transgenic mice

The transition from liver fibrosis to hepatocellular carcinoma (HCC) has been suggested to be a continuous and developmental pathological process. MicroRNAs (miRNAs) are recently discovered molecules that regulate the expression of genes involved in liver disease. Many reports demonstrate that miR‐483‐5p and miR‐483‐3p, which originate from miR‐483, are up‐regulated in HCC, and their oncogenic targets have been identified. However, recent studies have suggested that miR‐483‐5p/3p is partially down‐regulated in HCC samples and is down‐regulated in rat liver fibrosis. Therefore, the aberrant expression and function of miR‐483 in liver fibrosis remains elusive. In this study, we demonstrate that overexpression of miR‐483 in vivo inhibits mouse liver fibrosis induced by CCl₄. We demonstrate that miR‐483‐5p/3p acts together to target two pro‐fibrosis factors, platelet‐derived growth factor‐β and tissue inhibitor of metalloproteinase 2, which suppress the activation of hepatic stellate cells (HSC) LX‐2. Our work identifies the pathway that regulates liver fibrosis by inhibiting the activation of HSCs.     

Suitable internal control microRNA genes for measuring miRNA abundance in pig milk during different lactation periods

Determination of an optimal set/number of internal control microRNA (miRNA) genes is a critical, but often undervalued, detail of quantitative gene expression analysis. No validated internal genes for miRNA quantitative PCR (q-PCR) in pig milk were available. We compared the expression stability of six porcine internal control miRNA genes in pig milk from different lactation periods (1 h, 3 days, 7 days, 14 days, 21 days, and 28 days postpartum), using an EvaGreen q-PCR approach. We found that using the three most stable internal control genes to calculate the normalization factor is sufficient for producing reliable q-PCR expression data. We also found that miRNAs are superior to ribosomal RNA (rRNA) and snRNA, which are commonly used as internal controls for normalizing miRNA q-PCR data. In terms of economic and experimental feasibility, we recommend the use of the three most stable internal control miRNA genes (miR-17, -107 and -103) for calculating the normalization factors for pig milk samples from different lactation periods. These results can be applied to future studies aimed at measuring miRNA abundance in porcine milk.     

分离自甘肃天祝五台岭土壤的放线菌拮抗性的初步研究

从甘肃天祝县土壤中分离到的27株放线菌,作为测试放线菌拮抗性的供试茵株.抗菌试验表明,14株放线菌对6株革兰氏阳性菌和阴性菌以及白色念殊菌等指示菌有抗性.菌株WTL-4、WTL-20和WTL-26抗菌谱最广,WTL-4能抗3种革兰氏阳性菌,WTL-20能抗革兰氏阳性的金黄色葡萄球菌和单增李斯特菌、革兰氏阴性的沙门氏菌及真菌白色念殊菌,WTL-26能抗革兰氏阳性的金黄色葡萄球菌和单增李斯特菌及革兰氏阴性的沙门氏菌.抗肿瘤试验表明,有8株菌株对肿瘤细胞有抑制作用,其中抑制率在60%以上的菌株占18.5%.对抗肿瘤活性较高的3株菌WTL-4、WTL-14和WTL-15以及没有抗菌和抗肿瘤活性的菌株WTL-27进行了系统发育分析.从系统发育树可以看出,4株菌均属于链霉菌属(Streptomyces).菌株WTL-4与Streptomyces viridochromoqenes的相似性为98%;菌株WTL-14和WTL-15的相似性达到99.2%,它们与S.flavolimosus 174457的相似性达到99.4%;WTL-27与S.mycroflavus的相似性为99%.